Hydrogen-Bond-Directed Highly Stereoselective Synthesis of Z-Enamides via Pd-Catalyzed Oxidative Amidation of Conjugated Olefins Ji Min Lee, Doo-Sik Ahn, Doo Young Jung, Junseung Lee, Youngkyu Do, Sang Kyu Kim,* and Sukbok Chang* Contribution from the Center for Molecular Design and Synthesis, Department of Chemistry and School of Molecular Science (BK21), Korea AdVanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea Received June 14, 2006; E-mail: sangkyukim@kaist.ac.kr; sbchang@kaist.ac.kr Abstract: An efficient procedure for the preparation of Z-enamides has been developed, involving the reaction of primary amides with conjugated olefins using a Pd/Cu cocatalyst system. It was found that certain additives, such as phosphine oxides and phosphonates, increase the efficiency of the reaction in nonpolar solvents under an oxygen atmosphere, thus producing a variety of Z-enamides in high yields with excellent stereoselectivity under Wacker-type conditions. The oxidative amidation reaction has a broad substrate scope, allowing alkyl, aryl, and vinyl amides to react with olefins conjugated with ester, amide, phosphonate, and ketone groups. The notable preference for the formation of Z-enamides is presumably due to the presence of an intramolecular hydrogen bond between the amido proton and the carbonyl oxygen. The energy difference between two plausible σ-alkylamidopalladium intermediates, leading to Z- and E-isomeric enamide products, respectively, was calculated to be 4.18 kcal/mol. The -hydride elimination step is assumed to be a stereochemistry-determining step in the overall oxidative amidation process, with the energy level for the transition state leading to the Z-enamide being 5.35 kcal/mol lower than that leading to the E-isomer. The efficiency of photoisomerization between Z- and E-enamides was observed to be largely dependent on the substrates’ substituents, and certain E-enamides could be obtained in synthetically useful yields by photoirradiation of Z-isomers. Synthetic application of the present method was successfully demonstrated by a direct formal synthesis of cis-CJ-15,801. Introduction Hydrogen bonds serve as one of the most essential motifs both in molecular recognition and for defined organization of important molecules in chemistry and biology. 1 Although numerous examples of hydrogen-bonding-driven approaches have been reported in crystal engineering and self-assembly, 2 the use of this noncovalent interaction in catalysis has been less frequently investigated. In fact, only in recent years have hydrogen bonds been utilized as a key feature to control activity and/or selectivity in certain catalytic transformations, 3 such as Diels-Alder, epoxidation, aldol, Michael, hydrogenation, and cycloaddition reactions. 4 Enamides are widely present as a key structural moiety in numerous natural products, 5 such as palytoxin, 6a terpeptin, 6b aspergillamides, 6c chondriamides, 6d salicylihalamides, 6e apicu- laren A, 6f TMC-95A-D, 6g crocacins, 6h lansiumamide A, 6i storniamides, 6j and enamidoin. 6k In addition, enamides serve as highly versatile synthetic intermediates, especially in the forma- tion of heterocycles and in asymmetric synthesis for the generation of secondary or tertiary chiral amines. 7 As a result, several protocols have been devised for the preparation of (1) (a) Whitesides, G. M.; Simanek, E. E.; Mathias, J. P.; Seto, C. T.; Chin, D. N.; Mammen, M.; Gordon, D. M. Acc. Chem. Res. 1995, 28, 37-44. (b) Alkorta, I.; Rozas, I.; Elguero, J. Chem. Soc. ReV. 1998, 27, 163-170. (c) Wormer, P. E. S.; van der Avoird, A. Chem. ReV. 2000, 100, 4109- 4143. (d) Steiner, T. Angew. Chem., Int. Ed. 2002, 41, 48-76. (2) For selected recent reviews, see: (a) Subramanian, S.; Zaworotko, M. J. Coord. Chem. ReV. 1994, 137, 357-401. (b) Ariga, K.; Kunitake, T. Acc. Chem. Res. 1998, 31, 371-378. (c) Sherrington, D. C.; Taskinen, K. A. Chem. Soc. ReV. 2001, 30, 83-93. (d) Desiraju, G. R. Acc. Chem. Res. 2002, 35, 565-573. (e) Choi, K.; Hamilton, A. D. Coord. Chem. ReV. 2003, 240, 101-110. (3) (a) Adam, W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703-710. (b) Schreiner, P. R. Chem. Soc. ReV. 2003, 32, 289-296. (c) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520-1543. (4) (a) Bassani, D. M.; Darcos, V.; Mahony, S.; Desvergne, J.-P. J. Am. Chem. Soc. 2000, 122, 8795-8796. (b) Schuster, T.; Bauch, M.; Du ¨rner, G.; Go ¨bel, M. W. Org. Lett. 2000, 2, 179-181. (c) Rankin, K. N.; Gauld, J. W.; Boyd, R. J. J. Am. Chem. Soc. 2001, 123, 2047-2052. (d) Thadani, A. N.; Stankovic, A. R.; Rawal, V. H. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5846-5850. (e) Pihko, P. M. Angew. Chem., Int. Ed. 2004, 43, 2062- 2064. (5) Yet, L. Chem. ReV. 2003, 103, 4283-4306. (6) (a) Moore, R. E.; Bartolini, G. J. Am. Chem. Soc. 1981, 103, 2491-2494. (b) Kagamizono, T.; Sakai, N.; Arai, K.; Kobinata, K.; Osada, H. Tetrahedron Lett. 1997, 38, 1223-1226. (c) Toske, S. G.; Jensen, P. R.; Kauffman, C. A.; Fencial, W. Tetrahedron. 1998, 54, 13459-13466. (d) Davyt, D.; Entz, W.; Fernandez, R.; Mariezcurrena, R.; Mombru, A. W.; Saldana, J.; Dominguez, L.; Coll, J.; Manta, E. J. Nat. Prod. 1998, 61, 1560-1563. (e) Erickson, K. L.; Beutler, J. A.; Cardellina, I. I., J. H.; Boyd, H. M. R. J. Org. Chem. 1997, 62, 8188-8192. (f) Kunze, B.; Jansen, R.; Sasse, F.; Hofle, G.; Reichenbach, H. J. Antibiot. 1998, 51, 1075- 1080. (g) Kohno, J.; Koguchi, Y.; Nishio, M.; Nakao, K.; Kuroda, M.; Shimizu, R.; Ohnuki, T.; Komatsubara, S. J. Org. Chem. 2000, 65, 990- 995. (h) Kunze, B.; Jansen, R.; Hofle, G.; Reichenbach, H. J. Antibiot. 1994, 47, 881-886. (i) Lin, J.-H. Phytochemistry 1989, 28, 621-622. (j) Palermo, J. A.; Brasco, M. F. R.; Seldes, A. M. Tetrahedron 1996, 52, 2727-2734. (k) Koshino, S.; Koshino, H.; Matsuura, N.; Kobinata, K.; Onose, R.; Isono, K.; Osada, H. J. Antibiot. 1995, 48, 185-187. Published on Web 09/02/2006 12954 9 J. AM. CHEM. SOC. 2006, 128, 12954-12962 10.1021/ja0639315 CCC: $33.50 © 2006 American Chemical Society